3-Phenyl-3-hydroxypropylamine is an important intermediate for the synthesis of a variety of antidepressant drugs such as fluoxetine, tomoxetine and nisoxetine etc. Fluoxetine, tomoxetine and nisoxetine are among the most important pharmaceuticals for the treatment of psychiatric disorders (depression, anxiety, alcoholism) and also metabolic problems (obesity and bulimia) [(a) Zerbe, R. L.; Rowe, H.; Enas, G. G.; Wong, D.; Farid, N.; Lemberger, L. J. Pharmacol. Exp. Ther. 1985, 232, 139; (b) Stark, P.; Hardison, C. D. Clin. J. Psychiatry 1985, 46, 53; (c) Robertson, D. W.; Jones, N. D.; Swrtzendruber, J. K.; Yang, K. S.; Wang, D. T. J. Med. Chem. 1988, 31, 185; (d) Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31, 1412].
In the prior-art the synthesis of 3-phenyl-3-hydroxypropylamine segment of fluoxetine and related analogues has been accomplished employing various synthetic strategies. A commonly used strategy for the synthesis of N-methyl-3-phenyl-3-hydroxypropylamine is to employ the reduction of ethylbenzoylacetate with a metal hydride followed by amidation, (G. Magnone, EP 380924, 8 Aug. 1990; Kumar, A. et al Tetrahedron Lett 1991, 32, 1901; Kumar, A. et al Indian J. Chem 1992, 31B, 803; Chenevert, R. et al Tetrahedron 1992, 48, 6769), enzymatic reduction of ethyl benzoylacetate with a chiral ligand e.g. (−)-DIP-chloride (Hilborn, J. W. U.S. Pat. No. 5,936,124, 1999).
In another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine can be obtained from asymmetric reduction of β-chloropropiophenone with BH3 and chiral oxazoborolidine and subsequent substitution with methyl amine (Corey, E. J. et al Tetrahedron Lett 1989, 30, 5207).
In yet another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine was obtained by enzymatic resolution process of β-chloropropiophenone and subsequent substitution with methylamine (Schneider, M. P. et al Tetrahedron Asymmetry 1992, 3, 525).
In still another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine was obtained by asymmetric epoxidation of cinnamyl alcohol and regioselective reductive opening of epoxide with Red-Al (Sharpless K. B. et al J. Org. Chem. 1988, 53, 4081; Young, J. W. WO92-US888, 1992, US-91-793036, 1991).
In another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by the reduction of 3-phenyl-3-hydroxypropanenitrile (Koenig, T. M. et al Tetrahedron Lett. 1994, 35, 1339; Mitchell D. et al Synth. Commun. 1995, 25, 1231).
In yet another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by asymmetric hydrogenation of β-aminoketone catalyzed by cationic Rhodium (1) {AMPP} complex (Devocelle, M. et al Synlett 1997,1307).
In still another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by the asymmetric reduction of methyl-3-benzoylpropionate and subsequent conversion of product to amide and Hoffman rearrangement (Hilborn, J. M. Tetrahedron Lett. 2001, 42, 8919).
Tomoxetine has been prepared via reduction of phenyl haloalkyl ketones with diisopinocamphenyl haloboranes as key steps. The intermediate phenyl haloalkylketone was prepared in 75% yield and 97% ee (Brown, H. C. et. al U.S. Pat. No. 4,868,344, 1989; J. Org. Chem. 1988, 53, 2916). The same intermediate was prepared by Baker's yeast reduction and was further used for the synthesis of (R)-fluoxetine and (R)- and (S)-fenfluramine (Fronza, G. et. al J. Org. Chem., 1991, 56, 6019). In another prior-art method, fluoxetine hydrochloride is manufactured catalytically by hydrogenating 2-benzoyl-N-benzyl-N-methylethylamine in ethylacetate under H pressure of 5 bar using Pt/C or Pd-Pt/C catalyst as key step (Kairisalo, P. J. FI 81083, 1990).
In yet another prior-art method, the (S)-3-amino-1-phenyl-propanol was prepared by the reaction of (S)-1-phthalimido-1-phenyl-propanol and anhydrous N2H4 in ethanol. This intermediate was subsequently used for the synthesis of fluoxetine derivatives (Fuller, R. W. et al EP 369685, 1990).
In still another prior-art method, the N-methyl-3-phenyl-3-hydroxypropylamine was prepared by the condensation of PhCH(OH)CH2CH2NMe2 with ClCO2Et and subsequent hydrolysis (Schwartz, E. EP 529842, 1993).
In prior-art method, the optically active fluoxetine was prepared employing N-methyl-3-phenyl-3-hydroxypropionamide as a precursor which in turn was prepared by lipase catalyzed resolution of PhCH(OH)CH2COOEt (Yashida, N. Jpn. Kokai Tokkyo Koho JP 04005268, 1992).
Fluoxetine and its analogs are prepared by the etherification of 1-phenyl-3-(N-methylamino)-propan-1-ol with an arylating reagent (Agusti Cruz, A. ES 2120368, 1998; Arosio, R. U.S. Pat. No. 5,847,214, 1998).
In yet another prior-art method, N-methyl-3R-hydroxy-3-phenylpropylamine was prepared by resolving the racemic by S-(+)-mandelic acid (Ratz, A. M. EP 909754, 1999).
In still another prior-art method, 3-(methylamino)-1-phenyl-1-propanol was prepared by reaction of methylamine with 3-chloro-1-phenyl-1-propanol and subsequently converting into fluoxetine (Weber, B. WO 2000037425, 2000) or by converting chloropropiophenone into racemic alcohol and resolving it by the chiral separation (Gattuso, M. J. Jpn. Kokai Tokkyo Koho JP 2000290239, 2000).
Some of the major drawbacks of the methods known in the prior-art are such as:                (i) Multi-step synthesis        (ii) High cost of materials involved        (iii) Complicated reagents, longer reaction time and high reaction temperature        (iv) Difficulties involved in work-up procedure        (v) Difficulties involved in handling sophisticated reagents        (vi) Overall low yield of the desired compound        (vii) Poor enantio-selectivity        (viii) Lack of reusability of expensive reagents        
In view of the abovementioned drawbacks and disadvantages of the prior-art procedure, it is desirable to develop an improved, efficient and enantioselective process for the synthesis of 3-phenyl-3-hydroxypropylamine.